Novel triazolo pyrimidine compounds

ABSTRACT

The present invention relates to a pyrimidine compound (I) useful as a pharmaceutical intermediate, to a process for preparing said pyrimidine compound, to intermediates used in said process, and to the use of said pyrimidine compound in the preparation of pharmaceuticals.

The present invention relates to a pyrimidine compound useful as apharmaceutical intermediate, to a process for preparing said pyrimidinecompound, to intermediates used in said process, and to the use of saidpyrimidine compound in the preparation of pharmaceuticals.

The present invention provides a compound of formula (I):

The present invention also provides a process for preparing a compoundof formula (I), comprising reacting a compound of formula (II):

with a salt of a compound of formula (III):

in the presence of a suitable base (such as an alkali metal hydroxide(such as sodium or potassium hydroxide) a tertiary amine (such as atri(C₁₋₆ alkyl)amine, for example triethylamine)), a suitable solvent(such as an alcohol, such as an aliphatic alcohol containing from 1 to 6carbon atoms, for example ethanol), preferably at a temperature in therange 100-150° C. and, cohere necessary (for example when thetemperature exceeds the boiling point of the solvent), in a sealedsystem under autogenic pressure.

A suitable salt of a compound of formula (III) is a salt of a mineral ororganic acid. Suitable mineral acids include hydrochloric, hydrobromic,hydroiodic, nitric or sulphuric acid. A suitable organic acid is, forexample, an organic achiral acid such as acetic, trifluoroacetic, oxalicor p-toluenesulphonic acid, or an organic chiral acid such as L-tartaricacid, dibenzoyl-L-tartaric acid or di-p-toluoyl-L-tartaric acid.

In another aspect the present invention provides a process for preparinga compound of formula (I) comprising hydrogenating a compound of formula(IV):

wherein Ar is phenyl optionally substituted by halogen, C₁₋₄ alkyl orC₁₋₄ alkoxy; to give a compound of formula (II), and reacting thecompound of formula (II) with a compound of formula (III) (as describedabove) to provide the compound of formula (I).

The hydrogenation is preferably conducted using a heavy metal catalyst(such as platinum on carbon), in a suitable solvent (such as a C₁₋₆aliphatic alcohol, for example 2 propanol (iso-propanol)), at a suitabletemperature (such as 10-70° C., for example 20-50° C.) and at a suitablepressure (such as 1-5 bar, for example about 3 bar).

A compound of formula (IV) can be prepared by chlorinating a compound offormula (VIII):

wherein Ar is as defined above, with a suitable chlorinating agent (suchas phosphorus oxychloride) in the presence of a suitable nitrogencontaining base (such as triethylamine, especially pyridine) and at asuitable temperature (such as in the range 50° C. to the boiling pointof phosphorus oxychloride; for example 70 to 90° C.). A compound offormula (VIII) can be prepared by routine adaptation of literaturemethods.

In a further aspect the present invention provides a process, ashereinbefore described, for the preparation of a compound of formula(II).

The compound of formula (I) can be used to prepare the pharmaceuticalcompound of formula (A):

as described below.

Thus, a compound of formula (A) can be prepared by deprotecting acompound of formula (V):

for example using a strong mineral acid (such as hydrochloric acid) in asuitable solvent (such as methanol or ethanol).

A compound of formula (V) can be prepared by coupling a compound offormula (VI) {or a salt thereof (such as a mandelate salt) from whichthe compound of formula (VI) is generated in situ}, with a compound offormula (VII):

for example in the presence of a suitable base (such as a tertiaryamine, such as a tri(C₁₋₆ alkyl)amine, for example triethylamine) and asuitable solvent (for example a polar solvent, such as an alcohol (suchas an aliphatic alcohol containing from 1 to 6 carbon atoms, for exampleethanol) or a nitrile (such as acetonitrile)) and at a suitabletemperature (such as a temperature in the range 10-40° C., for exampleambient temperature).

A compound of formula M) can be prepared by reacting a compound offormula (I) with an alkali metal nitrite (such as NaNO₂) or an organicnitrite (for example iso-amyl nitrite) in the presence of a suitableacid (such as acetic acid) and a suitable solvent (such as water or amixture of water and acetic acid) and at a suitable temperature (such asa temperature in the range −10 to 15° C., for example −10 to 10° C.).

Thus, in a further aspect the present invention provides the use of thecompound of formula (I) in a process for the preparation of the compoundof formula (A).

A salt of a compound of formula (III) can be prepared by reacting acompound of formula (III) with the necessary acid in a suitable solvent(such as water, an aliphatic alcohol containing 1 to 4 carbon atoms (forexample ethanol) or a simple ester (such as ethyl acetate)) at asuitable temperature (such as from 10 to 60° C., for example 30 to 50°C.).

A compound of formula (III) can be prepared by deprotecting a compoundof formula (IX):

for example by hydrogenation {such as with a heavy metal catalyst (suchas palladium on carbon) in the presence of a solvent (such as analiphatic alcohol containing 1 to 4 carbon atoms, for example ethanol)at ambient temperature at a suitable pressure (such as 1 to 3 bar, forexample 1.0 to 1.5 bar)}.

A compound of formula (IX) can be prepared by reducing a compound offormula (X):

wherein R* is C₁₋₄ alkyl (preferably ethyl), such as with a suitableborohydride (for example an alkali metal borohydride, such as lithiumborohydride), lithium aluminiumhydride or DIBAL-H in a suitable polarsolvent (such as tetrahydrofuran).

A compound of formula (X) can be prepared by reacting a compound offormula (XI):

with a suitable compound L-CH₂CO₂R* {wherein R* is C₁₋₄ alkyl(especially ethyl); and L is a leaving group, especially halogen (forexample bromo)}, in the presence of a suitable polar solvent (such astetrahydrofuran) and in the presence of a suitable base (such aspotassium tert-butoxide, sodium hydride or a C₁₋₆ alkyl lithiumspecies).

A compound of formula (XI) can be prepared by reacting a compound offormula (XII):

with benzyl chloroformate in the presence of a suitable base (such aspotassium carbonate) and a suitable solvent (such as a ketone (forexample 4-methyl-2-pentanone) or a hydrocarbon (for example toluene)).

In a still further aspect the present invention provides a process forthe preparation of a salt of a compound of formula (III) as hereinbeforedescribed.

In further aspects the present invention provides an intermediatecompound of formulae (II), (IV), (VII), (VIII), (X) or (XI), or a saltof a compound of formula (III).

The following Examples illustrate the invention.

EXAMPLE 1

This Example illustrates the preparation of2-{[(3aR,4S,6R,6aS)-6-amino-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]-dioxol-4-yl]oxy}-1-ethanol,L-tartaric acid salt (1:1).

Step a: Preparation of [3aS-(3aα,4α,6α,6aα)]-[tetrahydro-6-hydroxy-2,2-dimethyl-4H-cyclopenta-1,3-dioxol-4-yl]-carbamic-phenylmethylEster

Potassium carbonate (39.3 g) was added to a suspension of[3αR-(3aα,4α,6α,6aα)]-6-amino-tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxol,hydrochloride, (prepared as described in WO 9905142) (27.1 g) in4-methyl-2-pentanone (500 ml). Water (150 ml) was then added followed bydropwise addition of benzyl chloroformate (23.1 g). The reaction mixturewas stirred at room temperature for 4 hours before the organic phase wasseparated. The aqueous phase was extracted with 4-methyl-2-pentanone(2×5 ml). The combined organics were concentrated and the residue waspurified (SiO₂, dichloromethane:methanol, 95:5 to 90:10 as eluant) togive the subtitle compound (39.23 g).

¹H NMR (CDCl₃) δ 7.32 (5H, m), 5.65 (1H, br s), 5.10 (2H, br s), 4.59(1H, d), 4.48 (1H, d), 4.27 (1H, m), 4.19 (1H, br m), 2.24 (1H, br s),1.69 (1H, d), 1.41 (3H, s), 1.26 (3H, s).

Step b: Preparation of[3aS-(3aα,4α,6α,6aα)]-[2,2-dimethyl-6-(2-hydroxyethoxy)-tetrahydro-4H-cyclopenta-1,3-dioxol-4-yl]-carbamic Acid, PhenylmethylEster

Potassium tert-butoxide (3.6 g) in tetrahydrofuran (20 ml) was addedover 5 minutes to a solution of the product from Step (a)(39.23 g) intetrahydrofuran (200 ml). After 15 minutes, ethyl bromoacetate (3.7 ml)in tetrahydrofuran (10 ml) was added dropwise. The mixture was stirredat 0° C. for 10 minutes, then further ethyl bromoacetate was added (3.7ml×4). The reaction mixture was stirred at 0° C. a further 2 hours.

Lithium borohydride (2.79 g) was then added portionwise to the reactionmixture which was then stirred at <5° C. for 16 hours. Glacial aceticacid (23 g) was added dropwise to the cold mixture. After stirring for30 minutes, water (10 ml) was added dropwise and the resulting mixturewas stirred for 30 minutes. The phases were then separated and theaqueous phase was extracted with ethyl acetate. The combined organicswere washed with saturated sodium bicarbonate and brine, dried andconcentrated. The residue was purified (SiO₂, ethyl acetate:hexane,25:75 to 50:50 as eluant) to give the subtitle compound (38.6 g).

MS (APCI) 218 (M+H⁺, 100%).

Step c: Preparation of[3aR-(3aα,4α,6α,6aα)]-2-[[6-amino-2,2-dimethyl-tetrahydro-4H-cyclopenta-1,3-dioxol-4-yl]oxy]-ethanol(alternatively named:2-{[(3aR,4S,6R,6aS)-6-amino-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]-dioxol-4-yl]oxy}-1-ethanol)

A slurry of 5% palladium on charcoal (4 g) in ethanol was added to asolution of the product from Step (b) (39.96 g) in ethanol (250 ml) andthe mixture was hydrogenated at 1.2 (bar for 20 hours. The catalyst wasfiltered off and the filtrate was concentrated to give the subtitlecompound (23.65 g).

MS (APCI) 160 (M+H⁺, 100%).

Step d: Preparation of[3aR-(3aα,4α,6α,6aα)]-2-[[6-amino-2,2-dimethyl-tetrahydro-4H-cyclopenta-1,3-dioxol-4-yl]oxy]-ethanolL tartrate (alternatively named:2-{[(3aR,4S,6R,6aS)-6-amino-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]-dioxol-4-yl]oxy}-1-ethanol,L-tartaric Acid Salt (1:1))

A stirred solution of the product obtained in Step (c) (545 g) inethanol (3.81) was heated to 35° C. L-tartaric acid (352 g) was added(temperature rise to 45° C.) and the mixture was stirred at 40-45° C.for 1 h. The mixture was cooled to 20° C. and the resulting thick slurrystirred for 16 h then filtered. The collected solid was washed with twoportions of 2-propanol (300 ml, then 500 ml), sucked dry then dried invacuo at 40° C. to give the product as white crystals (728 g).

EXAMPLE 2

This Example illustrates the preparation oftrans-(1R,2S)-2-(3,4-difluorophenyl)-cyclopropylamine, R-mandelate salt(alternatively namedtrans-(1R,2S)-2-(3,4-difluorophenyl)cyclopropanaminium(2R)-2-hydroxy-2-phenylethanoate.

Step 1: Preparation of (E)-3-(3,4-difluorophenyl)-2-propenoic Acid

A stirred mixture of pyridine (15.5 kg) and piperidine (0.72 kg) wereheated to 90° C. Malonic acid (17.6 kg) was added, followed by slowaddition, over 50 minutes, of 3,4-difluorobenzaldehyde (12.0 kg). Thereaction mixture was stirred at 90° C. for a further 4 hours and 36minutes. Water (58.5 kg) was added and 32 litres of the pyridine/watermixture then was distilled out of the reactor under reduced pressure.The reaction mixture was acidified to pH 1 with 37% hydrochloric acid(6.4 kg) over a 40 minute period, then cooled to 25° C. with strongstirring. The solids were collected by filtration, washed twice with 1%hydrochloric acid (34.8 L per wash), once with water (61 L) and thendeliquored thoroughly in the filter. The product was then dried undervacuum at 40° C. for 24 hours and 40 minutes, affording 13.7 kg of thecrystalline product.

Step 2: Preparation of (E)-3-(3,4-difluorophenyl)-2-propenyl Chloride

A stirred mixture of (E)-3-(3,4-difluorophenyl)-2-propenoic acid (8.2kg), toluene (7.4 kg) and pyridine (0.18 kg) was heated to 65° C. andthen thionyl chloride (7.4 kg) was added over 30 minutes. The reactionwas stirred for a further 2 h 15 minutes after the addition wascomplete, then diluted with toluene (8.7 kg). Excess thionyl chloride,sulfur dioxide and hydrogen chloride were then distilled out, togetherwith toluene (10 L), under reduced pressure, yielding a solution of the(E)-3-(3,4-difluorophenyl)-2-propenoyl chloride (approximately 9 kg) intoluene.

Step 3: Preparation of (1R,2S,5R)-2-isopropyl-5-methylcyclohexyl(E)-3-(3,4-difluorophenyl)-2-propenoate

A solution of L-menthol (7.1 kg) in toluene (8.5 kg) was added over a 20minute period to the solution of (E)-3-(3,4-difluorophenyl)-2-propenoylchloride (prepared as in Step 2) and pyridine (0.18 kg, 2.28 mol)stirring at 65° C. The reaction mixture was stirred at 65° C. for afurther 4 hours and 40 minutes after the addition was complete, thencooled to 25° C. and stirred for a 14 hours. The solution was dilutedwith toluene (16 kg), washed with 5% aqueous sodium chloride (6.4 kg),then 6% sodium hydrogen carbonate (6.47 kg), then water (6.1 kg). Thesolution was dried azeotropically by distillation of the solvent (20 L)under reduced pressure. Dimethyl sulfoxide (33.9 kg) was added and theremaining toluene was distilled off under reduced pressure, affording47.3 kg of a solution of (1R,2S,5R)-2-isopropyl-5-methylcyclohexyl(E)-3-(3,4-difluorophenyl)-2-propenoate (approx. 13.3 kg) in dimethylsulfoxide.

Step 4: Preparation of dimethylsulfoxonium methylide(dimethyl(methylene)oxo-λ⁶-sulfane

Sodium hydroxide powder (1.2 kg), prepared by milling sodium hydroxidepellets in a rotary mill through a 1 mm metal sieve, andtrimethylsulfoxonium iodide (6.2 kg) were stirred in dimethyl sulfoxide(25.2 kg) under a nitrogen atmosphere at 25° C. for 90 min. The solutionwas used directly in the preparation of(1R,2S,5R)-2-isopropyl-5-methylcyclohexyltrans-2-(3,4-difluorophenyl)cyclopropanecarboxylate.

Step 5: Preparation of (1R,2S,5R)-2-isopropyl-5-methylcyclohexyltrans-2-(3,4-difluorophenyl)cyclopropanecarboxylate

A solution of (1R-2S,5R)-2-isopropyl-5-methylcyclohexyl(E)-3-(3,4-difluorophenyl)-2-propenoate (approximately 8.6 kg) indimethyl sulfoxide (approximately 27.9 kg) was added with stirring over20 minutes to a mixture of dimethylsulfoxonium methylide (approximately2.6 kg, prepared as described above), sodium iodide (approximately 4.2kg), water (approximately 500 g) and sodium hydroxide (approximately 56kg) in dimethylsulfoxide (27.7 kg) at 25° C. The reaction mixture wasstirred for a further 2 hours and 50 minutes at 25° C., then useddirectly for the preparation of(1R,2S,5R)-2-isopropyl-5-methylcyclohexyltrans-(1R,2R)-2-(3,4-difluorophenyl)cyclopropanecarboxylate.

Step 6: Preparation of (1R,2S,5R)-2-isopropyl-5-methylcyclohexyltrans-(1R,2R)-2-(3,4-difluorophenyl)cyclopropanecarboxylate

A crude solution of (1R,2S,5R)-2-isopropyl-5-methylcyclohexyltrans-2-(3,4-difluorophenyl)cyclopropanecarboxylate produced asdescribed in step 5 was heated with stirring from 25° C. to 50° C. overa 1 hour period and the temperature was maintained for a further hour.The mixture was then cooled with stirring from 50° C. to 35° C. over 4hours, kept at 35° C. for 1 hour, then cooled to 26° C. over 4 hours,kept at 26° C. for 1 hour, then cooled to 19° C. over 3 hours and keptat 19° C. for 5 hours and 10 minutes. The product was collected byfiltration, affording a crystalline solid (2.7 kg) which was shown tocontain a mixture of (1R,2S,5R)-2-isopropyl-5-methylcyclohexyltrans-(1R,2R)-2-(3,4-difluorophenyl)cyclopropanecarboxylate (1.99 kg)and (1R,2S,5R)-2-isopropyl-5-methylcyclohexyltrans-(1S,2S)-2-(3,4-difluorophenyl)cyclopropanecarboxylate (85 g).

Step 7: Preparation oftrans-(1R,2R)-2-(3,4-difluorophenyl)cyclopropanecarboxylic Acid

(1R,2S,5R)-2-isopropyl-5-methylcyclohexyltrans-(1R,2R)-2-(3,4-difluorophenyl)-cyclopropanecarboxylate (9.6 kg,91.8% diastereomeric excess) was dissolved in ethanol (13.8 kg) andheated with stirring to 46° C. 45% aqueous sodium hydroxide (3.1 kg) wasadded over a 20 minute period and the mixture was stirred for a further2 hours and 27 minutes. Solvent (28 L) was distilled out of the mixtureunder reduced pressure, then the mixture was cooled to 24° C. anddiluted with water (29.3 kg), after which the liberated menthol wasextracted into toluene (3 washes of 3.3 kg each). The remaining aqueousmaterial was acidified to pH 2 with 37% hydrochloric acid (3.3 L) andthe product was extracted into toluene (8.6 kg, then 2 more washes of4.2 kg and 4.31 kg). The combined toluene extracts were washed with 1%hydrochloric acid (4.9 L), then diluted with further toluene (4.2 kg)and azeotropically dried by distillation of the solvent (25 L) underreduced pressure. A final dilution with toluene (24.2 kg) was followedby distillation of the solvent under reduced pressure (10 L) affording asolution containingtrans-(1R,2R)-2-(3,4-difluorophenyl)cyclopropanecarboxylic acid(approximately 3.45 kg) suitable for the production oftrans-(1R,2R)-2-(3,4-difluorophenyl)cyclopropanecarbonyl chloride.

Step 8: Preparation oftrans-(1R,2R)-2-(3,4-difluorophenyl)cyclopropanecarbonyl Chloride

Pyridine (70 ml) was added to a solution oftrans-(1R,2R)-2-(3,4-difluorophenyl)cyclopropanecarboxylic acid(approximately 3.45 kg) in toluene (approximately 12-15 kg)), preparedas described above and the mixture was then heated to 65° C. Thionylchloride (2.3 kg) was added over a period of 1 hour and the mixture wasstirred at 70° C. for 3 hours. Thionyl chloride (0.5 kg) was added andthe mixture was stirred a further 2 hours at 70° C. A final aliquot ofthionyl chloride (0.5 kg) was added and the reaction mixture was stirredfor 1 hour at 70° C., then cooled to 40° C. Periodic additions oftoluene (45 kg, 3 additions of 15 kg each) were made during distillationof solvent (approximately 60 L) from the mixture under reduced pressure,then the solution oftrans-(1R,2R)-2-(3,4-difluorophenyl)cyclopropanecarbonyl chloride(approximately 3.8 kg) in toluene (approximately 6-9 L) was cooled to20° C.

Step 9: Preparation oftrans-(1R,2R)-2-(3,4-difluorophenyl)cyclopropanecarbonyl Azide

A solution of trans-(1R,2R)-2-(3,4-difluorophenyl)cyclopropanecarbonylchloride (approximately 3.8 kg) in toluene (approximately 6-9 L),prepared in Step 8, at 1° C. was added over a period of 74 minutes to amixture of sodium azide (1.24 kg), tetrabutylammonium bromide (56 g) andsodium carbonate (922 g) in water (6.2 kg), stirring at 1.5° C. Themixture was stirred at 0° C. for 1 hour and 55 minutes, then the aqueouslayer was diluted with cold water (3.8 kg), stirred briefly, thenseparated. The toluene layer was washed once more at 0° C. with water(3.5 kg), then with 20% aqueous sodium chloride (3.8 L), then stored at3° C. for further use.

Step 10: Preparation oftrans-(1R,2S)-2-(3,4-difluorophenyl)cyclopropylamine

A cold solution oftrans-(1R,2R)-2-(3,4-difluorophenyl)cyclopropanecarbonyl azide preparedas described in Step 9 was added over a period of 41 minutes to toluene(6.0 kg) stirring at 100° C. The mixture was stirred for a further 55minutes at 100° C., then cooled to 20° C. and added over a period of 2hours and 15 minutes to hydrochloric acid (3M, 18.2 kg) stirring at 80°C. After 65 minutes the solution was diluted with water (34 kg) andcooled to 25° C. The toluene layer was removed and the aqueous layer wasbasified to pH 12 with 45% aqueous sodium hydroxide (3.8 kg) and theproduct was then extracted into ethyl acetate (31 kg) and washed twicewith water (13.7 kg per wash), affording a solution containingtrans-(1R,2S)-2-(3,4-difluorophenyl)cyclopropylamine (2.6 kg, 91.8%enantiomeric excess) in ethyl acetate (29.5 L).

Step 11: Preparation oftrans-(1R,2S)-2-(3,4-difluorophenyl)cyclopropanaminium(2R)-2-hydroxy-2-phenylethanoate

R-(−)-Mandelic acid (2.26 kg) was added to a solution containingtrans-(1R,2S)-2-(3,4-difluorophenyl)cyclopropylamine (2.6 kg, 91.8%enantiomeric excess), stirring at 17° C. in ethyl acetate (45.3 L). Themixture was stirred at 25° C. for 3 hours and 8 minutes, then filteredand washed twice with ethyl acetate (13.8 kg total) The crystallineproduct was dried at 40° C. under reduced pressure for 23 hours,affording trans-(1R,2S)-2-(3,4-difluorophenyl)-cyclopropanaminium(2R)-2-hydroxy-2-phenylethanoate (4.45 kg).

EXAMPLE 3

This Example illustrates the preparation of4,6-dichloro-2-(propylsulfanyl)-5-pyrimidinamine.

Step 1: 4,6-Dihydroxy-2-(propylsulfanyl)pyrimidine

Water (670 ml) was added to 2-thiobarbituric acid (200 g). The resultingmixture was stirred and sodium hydroxide (126.3 g) was added inportions. The mixture was stirred for 40 min. then diluted with water.1-Methyl-2-pyrrolidinone (400 ml) and 1-iodopropane (140.9 ml) were thenadded. The resulting slurry was stirred at 20° C. for 22 h. The pH ofthe mixture was then adjusted to 6.5 by addition of 1M HCl (600 ml) over30 min, then to pH 2.5 by the addition of 6 M HCl (180 ml) over afurther 30 min. The resulting slurry was stirred for 18 h and theproduct was isolated by filtration and washed successively with water(4×100 ml), ethanol (200 mm) and water (2×200 ml). The product was driedunder reduced pressure overnight at 50° C. to yield the title product asa white powder (185 g).

Step 2:4,6-Dihydroxy-5-[(E)-2-(4-methylphenyl)diazerryl]-2-(propylsulfanyl)pyrimidine

Ethanol (25 ml), 4,6-dihydroxy-2-(propylsulfanyl)pyrimidine (Step 1; 5g) and water (25 ml) were stirred together at room temperature. Sodiumhydroxide (1.02 g) was added and a clear solution obtained. Theresulting solution was cooled to 0° C. and then sodium acetate (9.42 g)was added to give Solution A.

In a separate vessel, a solution of p-toluidine (3.01 g) in water (10ml) was prepared. To this was added concentrated hydrochloric acid (37%w/w aqueous solution; 8.45 ml). The resulting mixture was cooled to 0°C., and a solution of sodium nitrite (2.16 g) in water (10 ml) wascooled to 0° C. and added dropwise to the toluidine—containing reactionmixture over 30 minutes. The temperature during the addition was keptbetween 0 and 5° C. The resulting mixture was cooled to 0° C. and addedto the cold (0° C.) Solution A (the temperature rose to 8° C.). Theresulting yellow suspension was stirred overnight and the pH of themixture was adjusted to pH 1 by addition of 6 M HCl. The mixture wasfiltered and the collected product washed with water (25 ml) ethanol (10ml). The product was dried under reduced pressure at 50° C. over 24 h togive the product as a yellow solid (6.97 g).

Step 3:4,6-Dichloro-5-[(E)-2-(4-methylphenyl)diazenyl]-2-(propylsulfanyl)pyrimidine

Pyridine (2.58 ml) was added to a stirred, heated (70° C.) slurry of4,6-dihydroxy-5-[(E)-2-(4-methylphenyl)diazenyl]-2-(propylsulfanyl)pyrimidine(Step 2, 5 g) in toluene (15 ml). Phosphorous oxychloride (18.7 ml) wasadded dropwise to the mixture over 15 min (exotherm to 94° C.). Thereaction mixture was heated for a further 4.5 h-then evaporated. Theresidue was azeotroped twice with toluene (2×30 ml). The residue wasdissolved in toluene (50 ml) and filtered to remove some solids. Thecollected solid was washed with toluene and the combined filtrateswashed with water (30 ml) and saturated aqueous sodium bicarbonatesolution (30 ml). Evaporation gave the title product (4.98 g) as a redoil that slowly crystallised on standing.

Step 4: Preparation of 4,6-dichloro-2-(propylsulfanyl)-5-pyrimidinamine

A stirred solution of4,6-dichloro-5-[(E)-2-(4-methylphenyl)diazenyl]-2-(propylsulfanyl)pyrimidine(Step (3), 1.1 kg) in 2-propanol (16.6 kg) was hydrogenated for 1 h at40° C./3.2 bar over a platinum on carbon catalyst (0.81 kg, 50% w/wPt/C). The hydrogen gas pressure was released and the reactor flushedwith nitrogen. The reaction mixture was filtered. The collected solidwas washed with 2-propanol (1.7 kg) and the combined filtrates wereconcentrated under reduced pressure. The residual oil was cooled to 20°C. and dissolved in ethyl acetate (5 kg) and water (5.51) was added. ThepH of the stirred mixture was adjusted to pH 2 by the addition of 3Maqueous hydrochloric acid (800 ml). The phases were allowed to separateand the aqueous phase was discharged. Water (2.751) was added to theorganic phase and the pH was adjusted to 2 by the addition of a smallamount of 3M HCl (45 ml). The aqueous phase was separated and theorganic phase concentrated under reduced pressure at 30-50° C., to give4,6-dichloro-2-(propylsulfanyl)-5-pyrimidinamine as a reddish viscousoil containing ethyl acetate that was dissolved in ethanol (8.5 kg).Solvent (6.51 of ethanol/ethyl acetate) was then removed by distillationat reduced pressure. A further portion of ethanol (4.5 kg) leas added tothe residue and the distillation repeated to remove 6.5 l of solvent.The ethanol solution of the product was used without furtherpurification in the following step.

EXAMPLE 4

This Example illustrates the preparation of [1S-[1α, 2α, 3β(1S*,2R*),5β]]-3-[7-[2-(3,4-difluorophenyl)cyclopropyl-amino]-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-5-(2-hydroxyethoxy)cyclopentane-1,2-diol(alternatively names(1S,2S,3R,5S)-3-[7-{[(1R,2S)-2-(3,4-difluorophenyl)cyclopropyl]amino}-5-(propylsulfanyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl]-5-(2-hydroxyethoxy)-1,2-cyclopentanediol).

Step 1: Preparation of[3aR-(3aα,4α,6α,6aα)]-2-[[6-[[5-amino-6-chloro-2-(propylthio)-4-pyrimidinyl]amino]tetrahydro-2,2-dimethyl-3aH-cyclopenta[d][1,3]dioxol-4-yl]oxy]ethanol (alternatively named2-[((3aR,4S,6R,6aS)-6-{[5-amino-6-chloro-2-(propylsulfanyl)-4-pyrimidinyl]amino}-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)oxy]-1-ethanol

The ethanolic solution of4,6-dichloro-2-(propylsulfanyl)-5-pyrimidinamine, (prepared as inExample 3, Step 4) was added to2-{[(3aR,4S,6R,6as)-6-amino-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]-dioxol-4-yl]oxy}-1-ethanol,L-tartaric acid salt (1:1) (1.18 kg). To the resulting stirred thickslurry was charged triethylamine (0.95 kg) maintaining the temperaturebetween 20 and 25° C. The reactor was sealed and the temperatureincreased to 120-125° C. The reaction mixture was kept within thistemperature range for 30 h, then cooled to 75° C., and the pressurerelease. The temperature of the mixture was adjusted to 50° C. and thesolvent distilled off under reduced pressure at 30 to 40° C. Ethylacetate (4.95 kg) and water (5.51) were added, the pH of the mixtureadjusted to pH 5 by the addition of 3M hydrochloric acid (100 ml), andthe phases were separated. The organic-phase was washed with 15% w/wbrine (5.51), then separated. The organic phase was concentrated underreduced pressure (4.81 of solvent removed) to give2-[((3aR,4S,6R,6aS)-6-{[≡-amino-6-chloro-2-(propylsulfanyl)-4-pyrimidinyl]}-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxo-4-yl)oxy]-1-ethanolas a brown-red viscous oil containing ethyl acetate. The product is usedwithout further purification in the following step.

Step 2: Preparation of[3aR-(3aα,4α,6α,6aα)]-2-[[6-[7-chloro-5-(propylthio)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl]tetrahydro-2,2-dimethyl-3aH-cyclopenta[d][1,3]dioxol-4-yl]oxy]ethanol(alternatively named 2-({(3aR,4S,6R,6as)-6-[7-chloro-5-(propylsulfanyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl]-2,2-dimethyltetrahydro-3aH-cyclopenta-[d][1,3]dioxol-4-yl}oxy)-1-ethanol)

2-[((3aR,4S,6R,6aS)-6-{[5-Amino-6-chloro-2-(propylsulfanyl)-4-pyrimidinyl]amino}-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)oxy]-1-ethanol,as obtained in Step 1 was dissolved in acetic acid (5.75 kg) and water(650 ml). The resulting solution was cooled to 2° C. (with stirring) anda solution of sodium nitrite (232 g) in water (1.251) was added suchthat the mixture temperature was held below 7° C. The mixture was thenallowed to warm to 7° C. then ethyl acetate (8.9 kg) was added. Aqueouspotassium carbonate solution (41, 37% w/w) was added. The mixture wasseparated and the organic phase washed with further aqueous potassiumcarbonate solution (3.8 kg, 21% w/w). The aqueous phase was discardedand the organic phase concentrated under reduced pressure to give thesub-titled compound as a red-brown viscous oil used without furtherpurification in the following step.

Step 3: Preparation of {3aR-[3aα,4α,6α(1R*,2S*),6aα]}-2-[6-({7-[2-(3,4-difluorophenyl)cyclopropyl]amino-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl}tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxol-4-yl)oxy]ethanol(alternatively named2-({(3aR,4S,6R,6aS)-6-[7-{[(1R,2S)-2-(3,4-difluorophenyl)-cyclopropyl]amino}-5-(propylsulfanyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl]-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl}oxy)-1-ethanol)

trans-(1R,2S)-2-(3,4-Difluorophenyl)cyclopropanaminium(2R)-2-hydroxy-2-phenylethanoate (0.77 kg) was charged to a vesselfollowed by a solution of 2({(3aR,4S,6R,6aS)-6-[7-chloro-5-(propylsulfanyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl]-2,2-dimethyltetrahydro-3aH-cyclopenta-[d][1,3]dioxol-4-yl}oxy)-1-ethanol (prepared as in Step 2)dissolved in acetonitrile (3.85 kg). To the resulting stirred mixturewas added triethylamine (0.81 kg) at such a rate that the reactiontemperature was maintained between 20-25° C. The reaction mixture wasstirred for 13 h then concentrated at reduced pressure at 30° C. To theresidue was added ethyl acetate (8.1 kg) and water (4.61). The pH of thestirred two phase mixture was adjusted to pH 4 by the addition of 3M HCl(450 ml). The mixture was then allowed to settle and separate. Theaqueous phase was separated and the retained organic phase was washedwith 15% w/w aqueous sodium chloride solution (4.15 kg), the organicphase was concentrated under reduced pressure at 30-50° C. giving thecrude title compound as a red oil, that was used directly in the nextstep.

Step 4: Preparation of [1S-[1α,2α,3β(1S*,2R*),5β]]-3-[7-(3,4-difluorophenyl)-cyclopropylamino]-5-(propylthio)-3H-1,2,3-triazolo[4,5-pyrimidin-3-yl]-5-(2-hydroxyethoxy)cyclopentane-1,2-diol(alternatively named(1S,2S,3R,5S)-3-[7-{[(1R,2S)-2-(3,4-Difluorophenyl)cyclopropyl]amino}-5-(propylsulfanyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl]-5-(2-hydroxyethoxy)-1,2-cyclopentanediol)

Aqueous hydrochloric acid (3 M, 4.81), was added to a stirred solutionof2-({(3aR,4S,6R,6aS)-6-[7-{[(1R,2S)-2-(3,4-difluorophenyl)cyclopropyl]-amino}-5-(propylsulfanyl)-3H-[1,3]triazolo[4,5-d]pyrimidin-3-yl]-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl}oxy)-1-ethanol(1.931 kg) in methanol (13.4 kg), maintaining the temperature during theaddition between 20 and 25° C. The mixture was then stirred for 24 h at20° C. Sodium hydroxide (45% w/w aqueous solution; 780 ml) was thenadded to adjust the pH of the mixture to pH 7.2. The methanol was thenremoved by distillation at reduced pressure and ethyl acetate (14.3 kg)added. The mixture was heated to 45° and the aqueous layer separated.The organic phase was then washed 15% w/w aqueous sodium chloridesolution (7.2 kg). Ethyl acetate (101) was removed by distillation atreduced pressure. Fresh ethyl acetate (7.2 kg) was charged and themixture filtered. The filter was washed with ethyl acetate (1.5 kg). Thecombined filtartes were dried by repeated addition/distillation of ethylacetate. When the solution was dry, the product content of the ethylacetate solution was determined by a chromatographic assay technique andfound to contain 1016 g of product, the concentration of the ethylacetate was adjusted until a concentration of 5 ml ethyl acetate/g ofthe crude product was reached. The ethyl acetate solution was heated to47° C. and isooctane (2.5 ml/g product, 2540 ml) was then added over 15min. The resulting slurry was stirred for 30 min. then more iso-octane(2540 ml) was added over 5 mins. The resulting mixture was stirred at48-50° C. for 30 min then cooled to 20° C. over 3 h. The slurry wasstirred at 20° C. for 6.5 h then filtered and washed with a mixtureconsisting of iso-octane (1.25 kg) and ethyl acetate (1.6 kg). Thecollected solid was dried in vacuo to give the title compound (920 g).

If desired, the crude product can be further purified by employing oneof the following three methods.

Recrystallization from Ethyl Acetate/Iso-Octane

The crude product is dissolved in ethyl acetate (4.8 ml/g) at 55° C.,then filtered to remove particles. The clear solution is taken back tothe reactor for recrystallisation and the temperature is set at 50° C.iso-Octane is then added (4.8 ml/g) during 10 min. The slurry is allowedto stand for 30 minutes after which it is cooled to 20° C. during 2-3hours and finally the temperature is kept at 20° C. for about 30minutes. The product is then filtered and washed with iso-octane (2×15ml/g). The product is dried under reduced pressure at 50° C. giving pureproduct (>98% pure by h.p.l.c. analysis).

Slurry with N-Butyl Acetate

The crude product is suspended in n-butyl acetate 4 ml/g and stirred atroom temperature for 10 hours. The slurry is cooled to 0° C. during 34hours and kept at 0° C. for 1 hour. The product is filtered and washedwith 2 ml/g of cold n-butyl acetate (<0° C.). The product is then driedin vacuo at 50° C., giving pure product (>98% pure by h.p.l.c.analysis).

Slurry with Iso-Propanol

The crude product is suspended in iso-propanol 3 ml/g and stirred at 50°C. for 72 h. The slurry is then cooled to 20° C. during 3 hours and thetemperature is kept at 20° C. for about 30 minutes. The product is thenfiltered and washed with 1 ml/g of cold iso-propanol (<0° C.). Finally,the product is dried under reduced pressure at 50° C. giving pureproduct (>98% pure by h.p.l.c. analysis).

1. A compound of formula (I):


2. A process for preparing a compound of formula (I), comprisingreacting a compound of formula (II):

with a salt of a compound of formula (III):


3. A process for preparing a compound of formula (I) as claimed in claim2 comprising hydrogenating a compound of formula (IV):

wherein Ar is phenyl optionally substituted by halogen, C₁₋₄ alkyl orC₁₋₄ alkoxy; to give a compound of formula (II), and reacting thecompound of formula (II) with a compound of formula (III) to provide thecompound of formula (I).
 4. A process for preparing a compound offormula (II):

comprising hydrogenating a compound of formula (IV):

wherein Ar is phenyl optionally substituted by halogen, C₁₋₄ alkyl orC₁₋₄ alkoxy.
 5. A process for preparing a compound of formula (II) asclaimed in claim 2, comprising chlorinating a compound of formula(VIII):

wherein Ar is phenyl optionally substituted by halogen, C₁₋₄ alkyl orC₁₋₄ alkoxy, to provide a compound of formula (IV), and thenhydrogenating the compound of formula (IV).
 6. The use of a compound offormula (I) to prepare a compound of formula (A):

comprising: (a) reacting a compound of formula (I) with an alkali metalnitrite in the presence of a suitable acid to prepare a compound offormula (VII):

(b) coupling the compound of formula (VII) with a compound of formula(VI):

to provide a compound of formula (V):

(c) deprotecting a compound of formula (V) to provide the compound offormula (A).
 7. A process for preparing a salt of a compound of formula(III):

comprising reacting a compound of formula (III) with the necessary acid.8. A process for preparing a salt of a compound of formula (III):

comprising the steps: (a) preparing a compound of formula (XI):

by reacting a compound of formula (XII):

with benzyl chloroformate; (b) preparing a compound of formula (X):

by reacting a compound of formula (XI) with a compound L-CH₂CO₂R*{wherein R* is C₁₋₄ alkyl; and L is a leaving group}; (c) preparing acompound of formula (IX):

by reducing a compound of formula (X); (d) preparing a compound offormula (III):

by deprotecting a compound of formula (IX); and, (e) preparing a salt ofa compound of formula (III) by reacting the compound of formula (III)with the necessary acid.
 9. An intermediate compound of formula (II),(IV), (VII), (VIII), (X) or (XI) or a salt of a compound of formula(III).